分子动力学模拟揭示PFAS诱导PPARα激活的分子机制  

Molecular Dynamics Simulation Reveals the Molecular Mechanism of PFAS-induced PPARα Activation

作　　者：陈欢 何家乐 肖子君 苏利浩 陈景文[1] Chen Huan;He Jiale;Xiao Zijun;Su Lihao;Chen Jingwen(Key Laboratory of Industrial Ecology and Environmental Engineering(Ministry of Education),Dalian Key Laboratory on Chemicals Risk Control and Pollution Prevention Technology,School of Environmental Science and Technology,Dalian University of Technology,Dalian 116024,China)

机构地区：[1]工业生态与环境工程教育部重点实验室,大连市化学品风险防控及污染防治技术重点实验室,大连理工大学环境学院,大连116024

出　　处：《生态毒理学报》2024年第3期1-8,共8页Asian Journal of Ecotoxicology

基　　金：国家自然科学基金资助项目(22136001);国家重点研发计划项目(2022YFC3902100)。

摘　　要：全/多氟烷基化合物(PFAS)可通过激活过氧化物酶体增殖物激活受体α(PPARα)诱导肝毒性,然而PFAS与PPARα相互作用的分子机制尚不清晰。本研究基于高斯加速分子动力学(GaMD)和分子力学-广义波恩表面积法(MM-GBSA),计算了7种传统和新型PFAS与PPARα的结合自由能(ΔG_(bind)),结果发现ΔG_(bind)与PFAS激活PPARα的半数效应浓度的对数值(logEC_(50))之间存在显著的相关性(r=0.82,P<0.05)。此外,氟化碳原子的数量与ΔG_(bind)正相关,且含羧基的PFAS的ΔG_(bind)通常比含磺酸基的PFAS更低。通过分析结构稳定性、氢键分布和配体-残基接触,揭示了PFAS的激活活性与其在PPARα口袋内的结合模式直接相关。活性较强的PFAS,优先结合到由螺旋(H)H3,H7,H11和H12组成的口袋中,与ILE354,HIS440和CYS276等关键残基形成相互作用。结果有助于筛选具有PPARα激活效应的PFAS,支持PFAS类化学品的毒性效应评估。Per-and polyfluoroalkyl substances(PFAS)could induce hepatotoxicity through the activation of peroxisome proliferator-activated receptorα(PPARα).However,the molecular mechanism of PFAS-induced PPARαactivation remains unclear.This study calculated the binding free energy(ΔG_(bind))of seven legacy and emerging PFASs with PPARαbased on Gaussian accelerated molecular dynamics(GaMD)and molecular mechanics-generalized Born surface area(MM-GBSA).The results indicated a significant correlation(r=0.82,P<0.05)betweenΔG_(bind)and the logarithmic value of half maximal effective concentration(logEC_(50))of PFAS activating PPARα.Additionally,the number of fluorocarbon atoms positively correlated withΔG_(bind),and PFAS containing carboxyl groups generally had a lowerΔG_(bind)compared to those containing sulfonate groups.The activation activity of PFAS towards PPARαwas found to be directly associated with their binding patterns within the PPARαligand-binding pocket,as revealed through the analysis of structural stability,hydrogen bond distribution and ligand-residue contacts.PFAS with stronger activities were observed to preferentially bind within the pocket composed of H3,H7,H11 and H12,i nteracting with key residues such as ILE354,HIS440 and CYS276.These results contribute to the screening of PFAS with PPARαactivation effect,and support the evaluation of toxic effects of PFAS.

关 键 词：全/多氟烷基化合物 过氧化物酶体增殖物激活受体Α 肝毒性 分子动力学 

分 类 号：X171.5[环境科学与工程—环境科学]